tbuckley/cabot-search huggingface dataset:
P03.04.B Garcin syndrome and hippocampal-sparing WBRT: successful resolution of a rare case
Authors: E Bonzano, R Russo, S Colombo, A Francia, R Di Liberto, A Filippi
Journal: Neuro-Oncology (2022)

Abstract Background first case of a rare Garcin syndrome resolution in a young metastatic breast cancer(BC) patient treated with a hippocampal-sparing approach. Material and Methods we report a case of a 49-year-old caucasian female. The medical record review was relevant for BC diagnoses in 1997, when she was 26yo; complicated by bone and liver metastasis appeared in 2008. In March 2020, she was referred to our department complaining about increasingly worsening left otalgia with initial hearing loss, left facial numbness, and homolateral decreased facial sensitivity, left increased lacrimation, and tingling tongue. Clinical presentation was suggestive for a Guillain-Alajouanine-Garcin Syndrome (Garcin Syndrome), caused by a lytic lesion in the left sphenoid wing. A contrast MRI (02/04/2020) of the brain demonstrated a lytic lesions in the left sphenoid wing, that was noted to infiltrate surrounding bone of the sphenoid sinus wall, including clivus, left pterygoid process and petrous bone; two parietal and occipital bone lesions were identified with a partial leptomeningeal involvement. According to the good PS, she underwent to a hippocampal-sparing WBRT VMAT plus a sequential boost on sphenoid lesion. PTV and OARs were delineated according to a fused planning MRI/CT image. Bilateral hippocampal contours were generated on the set according to RTOG 0933 contouring atlas. After that, a hippocampal avoidance(HA) region was created by expanding the hippocampal contours by 5 mm in all directions according to Brown et al.The PTV-HA was defined as the WB parenchyma, meninges and skull, excluding the HA-region, dose prescription 30Gy/10fx; the PTV-Boost was defined as the sphenoidal metastases, dose prescription of sequential boost was 12Gy/4fx. VMAT was used to deliver the conformal RT plan. Planning priorities that should be followed were:Hippocampus, OpticChiasm, OpticNerve_L or OpticNerve_R, Lens_L or Lens_R. Results The neurological symptoms improved after the end of RT with a complete resolution two months later. At the last MRI, a year and a half from the end of RT, there was no evidence of brain lesion, and no neurological symptoms were referred. These are our results of plan sum: for PTV-HA D2%=43.43 Gy, D98%=26.36 Gy, V30=94.96%; for Hippocampus D100%=8.78 Gy, Dmax=17.24 Gy; for Left OpticNerve Dmax=33.51%; for Right OpticNerve Dmax=29.25%; for OpticChiasm Dmax=35.93%. Conclusion To our knowledge, this is the first described case using the VMAT technique to spare the hippocampus plus a boost in a rare case of Garcin Syndrome. Prevention of neurocognitive sequelae by hippocampal avoidance has shown promise in several studies as in this case. Sequential boost demonstrated to be feasible and effective.Advanced RT techniques may be used to customize a treatment that allows preserving cognitive impairment achieving good clinical results in the long-term survival of metastatic patients.
P02.06.B Calvarial metastases: overview of the different entities and the pre-, intra- and postoperative course
Authors: S Hunziker, I Nasi-Kordishti, M Tatagiba
Journal: Neuro-Oncology (2022)

Abstract Background Calvarial metastases are most often in cancer with systematic bony metastatic disease. Calvarial metastases occur via hematogenous spread, retrograde seeding through Batson’s venous plexus, or direct extension. A variety of different primary tumours can cause calvarial metastases. The lesions can be palpable on the skin, cause local swelling and, depending on the location, neurological deficits can also occur. The aim of this research is to present an overview of the different entities and the neurosurgical management. Material and Methods Retrospectively, all patients who underwent surgery on a calvarial metastasis in our department between 2004 and 2021 (n=22) were identified. Data on the morphological and histological findings as well as the pre-, intra- and postoperative course were gathered and analysed. Results Swelling (n=14), cosmetically disturbing (n=9), pain (n=6), neurological deficits (n=4), epilepsy (n=3) and B-symptoms (n=1) were the main complaints. 7 had no symptoms at the time of diagnosis. There was a side preference with most of the lesions occurring on the right (n=13), less on the left (n=5) or bilateral (n=4). Calvarial metastases are divided in primary lesions, originating in the bone and secondary lesions infiltrating the bone. The majority of lesions originated from the bone except two, which wer secondary infiltrating the bone. 20 were not limited to the bone, infiltrating adjacent tissue (skin 70%, dura 85%, brain 35%). 18 lesions were osteolytic except four, where no further description was provided. Intraoperatively, craniectomy or in case of biopsy a craniotomy was performed. 70% of cases required Dural plastic. Depending on history and location the operative approach was biopsy (n=1), extended (n=6), subtotal (n=1) or complete (n=14) resection. Intraoperative major bleeding occurred in 15 % of cases, all with macroscopic high vascularization; hemodynamically relevant (n=1), requiring LAE (n=1). Histologically most common were adenocarcinoma of the lung (n=5), mamma (n=3), prostate (n=2), sigma (n=1), rectum (n=1) and gastric (n=1). Melanoma (n=3), neuroblastoma (n=1) and clear cell renal carcinoma (n=2) were less common. Other rare primaries were carcinoma of the parotid (n=1), SCLC (n=1) and follicular thyroidal cancer (n=1). Postoperatively, further treatment was initiated depending on the primary tumour. Conclusion: Above mentioned clinical symptoms or the staging of a cancer leads to the diagnosis of calvarial metastasis. Preoperative imaging shows localisation and the degree of infiltration into adjacent tissues. Imaging results and the clinical symptoms determine the surgical strategy. But definitive diagnosis can only be made by histological analysis. After surgery, the histology, the extension of the primary tumour and the clinical condition of the person influence the kind of further treatment initiated.
OS06.7.A Underlying mechanisms of verbal fluency in glioma patients: language or executive functioning?
Authors: E Collée, E Van den Berg, E Visch-Brink, C Dirven, A Vincent, D Satoer
Journal: Neuro-Oncology (2022)

Abstract Background Glioma patients often suffer from cognitive deficits, such as in language and executive functioning (EF). A sensitive test to identify these deficits is verbal fluency (VF). In VF, participants are asked to generate as many unique words within a given semantic category (category fluency - CF) or starting with a given letter (letter fluency - LF) within one minute. While both language and EF play a role in VF, the relative contribution of both domains remains unclear. We aim to retrospectively investigate performance on VF and, for the first time, on Non-Verbal Fluency (NVF), requiring to connect 5 points in different patterns within three minutes. Additionally, we aim to explore the influence of language and EF on VF performance in glioma patients. Materials and Methods 69 adults with gliomas in eloquent areas underwent a comprehensive neuropsychological test-battery at 1-2 months before surgery (T1) and 3 (T2) and 12 months (T3) after surgery. The protocol consisted of VF (CF: animals, professions, LF: D-A-T/K-O-M), language tests (Repetition (Akense Afasie Test), Token Test, Boston Naming Test) and EF tests (Five Point Test, Trail Making Test, Stroop Colour-Word Test, Wisconsin Modified Card Sorting Task). VF and NVF performance were compared 1) to healthy population using one sample t-tests/Wilcoxon rank-tests (all patients), and 2) between T1, T2, and T3 with paired sample t-tests/Wilcoxon rank-tests (31 patients). Linear regression analyses were conducted to investigate the predictive value of language and EF on VF for all patients. Results Preoperatively, patients were impaired on all VF tasks. Especially CF profession performance was more prone to deterioration after surgery at T2 and T3. In contrast, NVF was intact and even improved after surgery (T1-T3, T2-T3). NVF (p = .032, EF) was a predictor for CF animals while the Token Test (p = .023, language) was a predictor for CF professions. Both NVF (p = .032, EF) and the Token Test (p = .004, language) were predictors for LF. Conclusion First, glioma patients were preoperatively impaired in VF but were preserved in NVF, as is in line with the literature. Secondly, CF professions appeared to be particularly sensitive to detect long-term postoperative decline. Thirdly, the main result of this study is that both language and EF mechanisms appeared to be responsible for VF performance in glioma patients. These findings are useful for interpreting VF impairment in glioma patients and for therapeutic interventions, suggesting a combination of language and EF training materials.
OS11.4.A Intrathecal delivery of dendritic cell vaccine eradicates tumor growth and protects against leptomeningeal disease re-inoculation in immunocompetent HER2+ and triple negative breast cancer leptomeningeal disease xenograft models
Authors: V Law, K Kodumudi, C Snyder, B Czerniecki, P Forsyth
Journal: Neuro-Oncology (2022)

Abstract Background Leptomeningeal disease (LMD) occurs in ~5% of patients with breast cancer (BC) and has a median survival of 2-4 months. We found a loss of the anti-HER2 and anti-HER3 CD4 Th1 immune responses in BC patients. In pre-clinical and clinical trials the administration of class II HER2 peptide-pulsed dendritic cell vaccine (HER2-DCV) partially restores anti-HER2 Th1 immune responses with pathologic complete responses in HER2+ BC patients. Here, we examined the intrathecal (IT) delivery of HER2/HER3-DCV in BC-LMD immunocompetent animal models. Material and Methods Luciferase-labeled HER2+ TUBO BCs were injected into the cisterna magna of BALB/c mice to produce LMD. We used our Murine Ommaya (mimics an Ommaya reservoir clinically in patients) for the IT administration of DCVs into the cerebral spinal fluid (CSF). Results BC-LMD mice were randomized into following groups: 1) HER2-DCV IT 2) HER3-DCV IT 3) HER2/HER3-DCV IT. The median survival of untreated (control) group was 15 days. All groups given DCV IT prolonged survival (p&amp;lt;0.001). Interestingly, HER2-/HER3-DCV IT was able to rescue disease mice (71% in HER2+ BC-LMD and 28% in triple negative breast cancer-LMD) and showed complete tumor regression. Some surviving mice were immune to subsequent tumor rechallenge. In mice CSF, we found evidence of CD4+ and CD8+ T-cells infiltration, and robust IFN-gamma and IL18 response upon DCV treatment. Conclusion Our preclinical data supported a clinical trial (submitted) of the IT delivery of DCV in BC patients with LMD.
P07.01.A Topical Fluorescent Probe for Visualization of Glioblastoma
Authors: D Kim
Journal: Neuro-Oncology (2022)

Abstract Background Glioblastoma (GBM) is the most aggressive form of cancer that originates within the central nervous system (CNS). GBM represents 15% of all primary brain tumors, but the cause is unclear, and there is no clear way to prevent it. At the moment, various sophisticated and specific surgical procedures are being used, but there are relatively few simple methods. Material and Methods In this work, we used a turn-on type fluorescent probe that can sense cysteine (Cys) amino acid in the GBM site, and developed topical treatment methods for image-guided surgery (IGS). Results The probe can distinguish the GBM cells and disease sites in clinical samples from individual patients. Besides, the probe has no short or long-term toxicity and immune response. Conclusion The present findings hold promise for the application of the probe to a relatively simple and straightforward following of GBM at clinical sites.
P06.04.B Efficacy of Podoplanin-CAR-T Cells in<i>ex vivo</i> Patient Derived Glioblastoma Organoids
Authors: L Diener, N Goedert, T Schulz, C Monoranu, R Ernestus, C Hagemann, M Löhr, T Nerreter, V Dufner
Journal: Neuro-Oncology (2022)

Abstract Background Glioblastoma (GBM) is the most prevalent malignant brain tumor in adults. Recent immunotherapeutic approaches led to promising effects both in vitro and in preclinical animal models. However, tumor heterogeneity, antigen escape mechanisms and complex interactions with the tumor microenvironment (TME) hinder their clinical breakthrough. Thus, patient derived ex vivo models are needed to test new therapeutical approaches. Genetically modified T cells expressing a chimeric antigen receptor (CAR) hold enhanced affinity for tumor associated antigens. As Podoplanin (PDPN) shows stable and increased expression in GBM, it is a suitable target antigen. When activated, CAR-T cells initiate the triad of cytokine release, T cell proliferation and target cell apoptosis. We evaluated the performance of PDPN-CAR-T cells in GBM patient derived organoids (PDO). Material and Methods PDOs were generated from freshly resected GBM tissue and could be cultured successfully up to several months. We assessed PDPN expression of PDOs via immunohistochemistry (IHC) prior to treatment. PDPN-CAR T cells were generated from peripheral blood mononuclear cells of healthy donors via lentiviral transduction and expansion. The transduction rate was assessed by flow cytometry prior to application. PDOs treated with untransduced T cells served as controls. PDOs were incubated with a preset number of PDPN-CAR T cells at a E:T ratio of 1:4 and were examined microscopically to register morphological disintegration after 48h. Immunofluorescence staining was conducted to detect proliferating CD4+ CART cells (CD4+/ Ki67+) after 72h and cytokine release of IFN-γ was determined via ELISA after 20h. Results In total, PDOs from three patients were treated with PDPN-CART cells. All of them expressed the antigen according to IHC staining. All incubated PDOs presented clear disintegration of the circular organoid shape up to total dissolving, whereas control PDOs stayed intact. CD4+ CART cells showed extensive proliferation at a mean rate of 79.8% ± 6,59% which was significant for two PDOs in comparison to control PDOs (p = 0.48, p &amp;lt; 0.01). PDPNCART cells exhibited significantly elevated IFN-γ release in all PDOs (p &amp;lt; 0.01). Conclusion We here describe PDPN as a promising target and proved effectiveness of PDPN-CAR-T cells in an ex vivo 3D model. Additional ex vivo models like tumor slice cultures might be crucial to evaluate effectiveness of CAR-T cell therapy. PDPN-CAR-T cells should be tested in these ex vivo as well as in vivo GBM models alone and in a combined approach with CARs targeting additional antigens in order to overcome tumor heterogeneity.
OS07.4.A Regorafenib in recurrent glioblastoma patients: a multicentric real-life study
Authors: F Bruno, A Pellerino, E Pronello, R Palmiero, V Polo, R Vitaliani, E Trincia, V Internò, C Porta, R Soffietti, R Rudà
Journal: Neuro-Oncology (2022)

Abstract Background Few options are still available for recurrent glioblastoma (GBM). In the Italian phase 2 REGOMA trial, regorafenib improved overall survival, as compared to lomustine, for GBM patients at first progression after chemoradiation. Here, we present the results of a real-life multicentre study that analysed clinical and radiological features, response to treatments, tolerability, and outcome of a cohort of GBM patients treated with regorafenib at first tumour progression. Patients and Methods We enrolled GBM patients at first tumour progression in three Italian Institutions (Turin, Treviso, Bari). Regorafenib was administered following an escalation dose protocol (1st cycle: 80 mg/day for 2 weeks, then 120 mg/day for one week; 2nd cycle: 120 mg/day for 2 weeks, then 160 mg/day for one week; 160 mg/day from the 3rd cycle). MRI scans were obtained at baseline and every 3 months. Progression-free survival (PFS) and overall survival (OS) were defined as time from regorafenib initiation and disease progression or death. Results From January 2020 to January 2022, 66 GBM patients were included. Median age was 60.0 years. MGMTp methylation was found in 30 patients (45.5%). First-line treatment consisted in chemoradiation in 61 (92.4%), in upfront TMZ (3, 4.5%) or RT alone followed by TMZ (2, 3.0%). Median dose was 120 mg/day 21q28 day, which was lower than that used in REGOMA trial (149 mg). Median PFS (mPFS) was 2.7 months (2.4 - 3.0 95% CI) and median OS (mOS) 7.1 months (5.4 - 8.9 95% CI). Best RANO response to regorafenib was partial response (PR) in 10 (15.1%), stable disease in 14 (21.2%), and progressive disease in 42 (63.7%) patients. All PRs were observed within the first three months of treatment. Patients who completed treatment up the 6th, 9th, and 12th cycles were 20, 3 and 2, respectively. Forty-six (69.7%) patients presented adverse events of any grade, and 21 (31.8%) grade III-IV toxicity. The most frequent adverse events were fatigue (33.3%), hand-foot syndrome (27.3%), and liver enzymes increase (15.2%). Two patients only (3.0%) interrupted regorafenib due to toxicity.In a multivariable analysis, factors significantly associated with disease progression were higher age (p = 0.035) and absence of MGMTp methylation (p = 0.024). Conclusion In this real-life study on 66 patients, mPFS and mOS were similar to those of the 59 patients enrolled in the regorafenib arm of REGOMA trial (2.7 vs 2.0 months; 7.1 vs 7.4 months, respectively). However, we observed a higher rate of PRs as compared to REGOMA (15% versus 3.0%). Type and severity of adverse events were similar between the two studies. Moreover, we had a lower incidence of discontinuations of regorafenib due to toxicity, maybe attributable to the lower dose intensity.We are further analysing the data of MRI-perfusion, with the aim to explore whether it can predict an early response or progression in comparison to standard MRI.
OS03.7.A Clinical characteristics, treatment and long-term outcome of patients with brain metastases from thyroid cancer - an analysis of the Vienna Brain Metastasis Registry
Authors: L Wolff, A Steindl, K Dieckmann, B Gatterbauer, G Widhalm, A Berghoff, M Preusser, M Raderer, B Kiesewetter
Journal: Neuro-Oncology (2022)

Abstract Background The incidence of brain metastases (BM) in patients with thyroid cancer (TC) depends on the histological subtype. About 1% of patients with differentiated (DTC), 3% with medullary (MTC) and up to 10% with anaplastic thyroid cancer (ATC) develop BM. The diagnosis of BM drastically worsens the prognosis of TC. Given the rare incidence, little is known about the presentation and outcome of this cohort. Material and Methods Patients with a histologically verified diagnosis of TC and BM were identified from the Vienna Brain Metastasis Registry, a comprehensive database managed by the Division of Oncology, Medical University of Vienna, including patients with cerebral metastasis since 1990. Data were obtained from medical records comprising clinicopathological features, treatment, BM-specific characteristics and outcome. Results 20/6074 patients included in the registry had a diagnosis of TC and radiologically verified BM. 13/20 (65%) were female and the median age at diagnosis of TC and manifestation of BM was 56 years (range 21-75) and 68 years (range 45-75), respectively. In terms of histology, 18/20 (90%) had DTC, one MTC and one ATC. Interestingly, 10/18 DTC presented with follicular histology which underlines the more aggressive course of this rare subtype. 6/20 (30%) had BM at primary diagnosis (DTC n=5, ATC n=1), while the remaining developed BM during follow-up. The median time to diagnosis of BM was 2.6 years for DTC (range 0-42), 22 years in the MTC patient and 2 months for ATC. Regarding BM-specific characteristics, all but one patient had symptoms due to BM (neurological deficits n=11, increased intracranial pressure n=5, seizures n=3). Most patients (13/20) had a singular BM, commonly located in the left hemisphere (8/13), and only one had more than three BMs. Upfront treatment for BM was local therapy (resection n=9, stereotactic radiosurgery n=7, whole brain radiotherapy n=3); one patient received supportive care only. The median overall survival (mOS) from diagnosis of TC was 6 years for DTC (range 2.5 months-42 years), 33 years for the MTC and 9 months for the ATC. The mOS from diagnosis of BM was 14 months for DTC (1.8 months-16 years), 22 years for the MTC and 3 months for the ATC. Conclusion Few patients with TC develop BM, which present commonly as single lesion. While in general BM constitute a poor prognostic factor, individual patients experience long-term survival following local therapy. More information about the optimal management of BM in TC is needed to enable guideline recommendations.
OS01.5.A Neuron-specific enolase (NSE) and S100 serum levels in patients with active brain metastases from HER2-positive breast cancer treated with trastuzumab-deruxtecan (T-DXd): A biomarker analysis from the TUXEDO-1 trial
Authors: A S Berghoff, R Bartsch, J Furtner, M Marhold, E S Bergen, S Roider-Schur, A M Starzer, H Forstner, B Rottenmanner, K Dieckmann, Z Bago-Horvath, G Widhalm, A Ilhan-Mutlu, C Minichsdorfer, T Fuereder, C F Singer, A Weltermann, H Haslacher, T Szekeres, R Puhr, M Preusser
Journal: Neuro-Oncology (2022)

Abstract Background T-DXd is a novel antibody-drug conjugate with high activity in HER2-positive metastatic breast cancer. The prospective, single-arm, single-centre phase II TUXEDO-1 trial showed clinically relevant activity of T-DXd in HER2-positive BC pts with active BM with an intracranial response rate of 73.3%. This biomarker sub-study of TUXEDO-1 aimed to investigate changes in the extent of metastases-induced brain damage in patients with and without response to therapy by measuring the serum levels of two proteins constitutively expressed in the human brain and measurable upon brain damage in the blood serum: NSE and S100. Material and Methods We assessed serum NSE (sNSE) and serum S100 (sS100) levels in a total of 37 blood samples drawn at cycles 1, 4 and end of treatment (EOT) in all patients of the intent-to-treat population of the TUXEDO-1 trial using commercially available ELISA assays. Intracranial radiological response was centrally assessed by a board-certified neuro-radiologist using RANO criteria. sNSE and sS100 levels were compared between responders and non-responders using the Mann Whitney U test and a significance level of 0.05. Results At baseline, we detected no significant difference of sNSE or sS100 levels between T-DXd responders and non-responders, respectively. Baseline median sNSE level was 10.6 ng/ml (interquartile range (IQR) 8.6-12.2) in T-DXd responders as compared with median 12.5 ng/ml (IQR 12.2-12.9) in the non-responder group (n.s.). At cycle 4, corresponding numbers were 8.1 ng/ml in responding patients (IQR 7-11.2) and 12.7 ng/ml (IQR 12.2-12.9) in non-responders, respectively (p=0.009). No differences in sS100 levels were observed between the groups at any time point. Conclusion In patients showing intracranial objective response to T-Dxd, sNSE levels were significantly lower at cycle 4 as compared with non-responders, suggesting a reduction in metastases-induced brain damage as a direct treatment effect. sNSE may be a clinically useful biomarker for longitudinal assessment of brain metastasis burden.